The large number of literature references, patent applications as well as scientific publications proves the therapeutic importance of neuromuscular blocking agents.
The first important results of the research on steroidal neuromuscular blocking agents are described in the United Kingdom patent specification No. 1,138,605 or the equivalent Hungarian patent specification No. 154,368, respectively. In these patents, the synthesis of 2.beta.,16.beta.-bis-(amino)-3.alpha.,17.beta.-diacetoxy-5.alpha.-androsta ne derivatives and their quaternary salts are described. These compounds contain piperidino, morpholino or alkylamino groups in the 2- and 16-positions of the steroid skeletons. Thus, quaternary centers can be formed only on the nitrogens bound to the C-2 and C-16 carbon atom.
The synthesis described in the above-cited patent specifications and the biological results obtained are summarized in: J. Medicinal Chemistry 16, 1116 (1973).
From these compounds, pancuronium bromide (chemically,1'-[3.alpha.,17.beta.-bis(acetyloxy)-5.alpha.-androstane-2.bet a.,16.beta.-diyl]bis[1-methylpiperidinium]dibromide) became a therapeutically employed neuromuscular blocking agent with long duration and non-depolarizing mechanism of action.
Due to its shorter duration of action and lack of cardiovascular side effects, vecuronium bromide (chemically 1-[3.alpha.,17.beta.-bis(acetyloxy)-2.beta.-(1-piperidinyl)androstan-16.be ta.-yl]1-methylpiperidinium bromide hydrochloride), a derivative which is structurally close to pancuronium bromide, except that it contains a single quaternary group on the nitrogen connected to C-16 carbon atom, is more advantageous than pancuronium and other bisquaternary derivatives. The preparation of vecuronium is described in the Hungarian patent specification No. 181,847 which is equivalent to the European patent specification No. 0,008,824.
A more recent important result in the research of neuromuscular blocking drugs is published in the Hungarian patent specification No. 165,600. From the compounds published therein, the effectivity as well as the cardiovascular stability of pipecuronium bromide (chemically 4,4'-[3.alpha.,17.beta.-bis(acetyloxy)-5.alpha.-androstane-2.beta.,16.beta .-diyl]bis[1,1-dimethylpiperazinium]dibromide) exceed those of pancuronium bromide or vecuronium bromide.
The synthesis of quaternary derivatives of bis(amino)androstanes are furthermore described in the European patent specification Nos. 0,208,497, 0,330,253 and 0,288,102 as well as in the Hungarian patent specification Nos. 172,522 and 172,521. The compounds published in these latter patent applications cited have not been utilized in therapy.
The synthesis of quaternary derivatives of the so-called aza-aminosteroids having a different chemical structure is described in the Hungarian patent specification No. 175,287. In spite of their rapid onset and short duration of action, because of their unwanted cardiovascular effects, these latter compounds have not been used therapeutically.
In spite of the fact that pancuronium bromide, vecuronium bromide as well as pipecuronium bromide are widely used in clinical practice, there is a constant demand in medicine for compounds possessing more desirable properties (e.g. more rapid onset of action).
A neuromuscular blocking agent, favorable for clinical use, should have a non-depolarizing mechanism of action, should not have vagolytic or ganglion-blocking effects or cause histamine release and should possess good cardiovascular stability. Another demand is a rapid onset of action allowing earlier intubation. This, from the viewpoint of anesthetical practice, is an important safety factor. A further demand is for short duration of action, which contributes to controllability and safety of these compounds during surgical interventions.